2 – Bilirubin and other confounding factors
Is bilirubin the real cause of kernicterus?  Bilirubin
levels are normally high in newborn infants until
maturation of liver enzymes that can remove it.  The
so-called "blood-brain barrier" is the natural defense
that must have evolved long ago as a protection
against high neonatal bilirubin levels.

The blood-brain barrier is compromised by
substances, usually of smaller molecular size than
bilirubin, that are freely passed across capillary walls
into neurons and are directly toxic to metabolic
enzymes.  Protective mechanisms then go into action
to try to enhance oxygen and glucose transfer into
neurons, but these same mechanisms may then also
admit larger molecules like bilirubin.

Alcohol for example appears to be directly toxic to the
brain; the immediate response is vasodilation, which
increases blood flow most markedly in the inferior
colliculus (Grünwald et al 1993).  Likewise abnormal
metabolites produced in genetic metabolic disorders
like phenylketonuria (PKU) have a direct toxic effect,
as do substances like methyl mercury, common
compounds of lead, poisonous fumes like methyl
bromide, and "nerve gases" (Güttler 1984, Oyanagi et
al 1989, Bertoni & Sprenkle 1989, Cavanagh 1992,
Scremin et al 1991).

Kernicterus is perhaps best known as a condition
affecting babies born to Rh-negative mothers.  After
the birth of her first child, placental blood may leak
into the mother's bloodstream, and the Rh-negative
mother then produces antibodies to this factor if the
baby is Rh-positive.  In subsequent births maternal
antibodies can leak into the baby's blood stream and
destroy the baby's red blood cells with resulting high
levels of bilirubin.  A much heralded treatment for this
was devised in the 1960s (Mittendorf and Williams
1991), the now well-known RhoGAM injection given to
Rh negative mothers; this replaced the earlier and
riskier total replacement of affected infants' blood
(Pearson 1998).

Before antibodies to the Rh factor were discovered as
a cause of increased bilirubin levels in newborn
infants, Zimmerman and Yannet (1933) summarized a
large number of case reports many of which had
emphasized that staining by bilirubin was secondary to
factors like anoxia or sepsis that produced necrotic
lesions in the brain (Orth 1875, Schmörl 1904).  
Zimmerman and Yannet commented, "This differs in
no way from the well known fact that any intravital dye
will localize in zones of injury and will leave unstained
tissues which are not damaged," [p757].

Bilirubin does not appear to be directly toxic to
capillary cell walls or neurons, but it is clearly admitted
once the normal barriers are broken down.

A placental barrier prevents mixing of maternal and
infant blood throughout pregnancy.  Why this barrier
should ever break down during birth of the baby also
merits fuller investigation.  The human invention of
clamping the umbilical cord at birth increases blood
pressure in the placenta causing small hemorrhages
in the placenta that allow passage of the infant's blood
into the mothers circulation with subsequent formation
of maternal antibodies that can likewise leak across
the placenta in subsequent pregnancies (Dunn 1966).

Many women have questions and concerns about
modern management of childbirth.  What we need are
more scientific investigations of nature's methods and
their evolution in preservation of our species
(Wickham 2001).

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3. Grünwald F et al (1993)
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